tbuckley/cabot-search huggingface dataset:
Duodenal macrophages control dietary iron absorption via local degradation of transferrin
Authors: Nyamdelger Sukhbaatar, Maria Schöller, Stephanie Deborah Fritsch, Monika Linke, Stefanie Horer, Manuela Träger, Mario Mazic, Stephan Forisch, Karine Gonzales, Jan Pascal Kahler, Carina Binder, Caroline Lassnig, Birgit Strobl, Mathias Mueller, Barbara Scheiber-Mojdehkar, Claudia Gundacker, Stefanie Dabsch, Renate Kain, Markus Hengstschläger, Steven Verhelst, Günter Weiss, Igor Theurl, Thomas Weichhart
Journal: Blood (2023)

Iron is an essential cellular metal that is important for many physiological functions including erythropoiesis and host defense. It is absorbed from the diet in the duodenum and loaded onto transferrin, the main iron transport protein. Inefficient dietary iron uptake promotes many diseases, but mechanisms regulating iron absorption remain poorly understood. By assessing mice that harbor a macrophage-specific deletion of the tuberous sclerosis complex 2 (Tsc2), a negative regulator of mTORC1, we found that these mice possessed various defects in iron metabolism including defective steady state erythropoiesis and a reduced saturation of transferrin with iron. This iron-deficiency phenotype was associated with an iron import block from the duodenal epithelial cells into the circulation. Activation of mTORC1 in villous duodenal CD68+ macrophages induced serine protease expression and promoted local degradation of transferrin, whereas depletion of macrophages in mice increased transferrin levels. Inhibition of mTORC1 with everolimus or serine protease activity with nafamostat restored transferrin levels in the Tsc2-deficient mice as well as transferrin saturation. Physiologically, transferrin levels were regulated in the duodenum during the prandial process and Citrobacter rodentium infection. These data suggest that duodenal macrophages determine iron transfer to the circulation by controlling transferrin availability in the lamina propria villi.
Polymeric Phthalocyanine‐Based Nanosensitizers for Enhanced Photodynamic and Sonodynamic Therapies
Authors: Shuxin Liu, Jinjuan Ma, Evelyn Y. Xue, Shaolei Wang, Yubin Zheng, Dennis K. P. Ng, Aiguo Wang, Nan Zheng
Journal: Advanced Healthcare Materials (2023)

Photodynamic therapy and sonodynamic therapy are two highly promising modalities for cancer treatment. The latter holds an additional advantage in deep-tumor therapy owing to the deep penetration of the ultrasonic radiation. The therapeutic efficacy depends highly on the photo/ultrasound-responsive properties of the sensitizers as well as their tumor-localization property and pharmacokinetics. A novel nanosensitizer system based on a polymeric phthalocyanine (pPC-TK) is reported herein in which the phthalocyanine units are connected with cleavable thioketal linkers. Such polymer could self-assemble in water forming nanoparticles with a hydrodynamic diameter of 48 nm. The degradable and flexible thioketal linkers could effectively inhibit the π-π stacking of the phthalocyanine units, rendering the resulting nanoparticles an efficient generator of reactive oxygen species upon light or ultrasonic irradiation. The nanosensitizer could be internalized into cancer cells readily, inducing cell death by efficient photodynamic and sonodynamic effects. The potency is significantly higher than that of the monomeric phthalocyanine (PC-4COOH). The nanosensitizer could also effectively inhibit the growth of tumor in liver tumor-bearing mice by these two therapies without causing noticeable side effects. More importantly, it could also retard the growth of a deep-located orthotopic liver tumor in vivo by sonodynamic therapy.
Deep Brain Stimulation for Obsessive-Compulsive Disorder and Depression
Authors: Sameer A. Sheth, Helen S. Mayberg
Journal: Annual Review of Neuroscience (2023)

The field of stereotactic neurosurgery developed more than 70 years ago to address a therapy gap for patients with severe psychiatric disorders. In the decades since, it has matured tremendously, benefiting from advances in clinical and basic sciences. Deep brain stimulation (DBS) for severe, treatment-resistant psychiatric disorders is currently poised to transition from a stage of empiricism to one increasingly rooted in scientific discovery. Current drivers of this transition are advances in neuroimaging, but rapidly emerging ones are neurophysiological—as we understand more about the neural basis of these disorders, we will more successfully be able to use interventions such as invasive stimulation to restore dysfunctional circuits to health. Paralleling this transition is a steady increase in the consistency and quality of outcome data. Here, we focus on obsessive-compulsive disorder and depression, two topics that have received the most attention in terms of trial volume and scientific effort.
Plasma Insulin Concentration in Newborns and Children and Age at Menarche
Authors: Guoying Wang, Sally Radovick, Jessie P. Buckley, Russ Hauser, Paige L. Williams, Xiumei Hong, Colleen Pearson, William G. Adams, Xiaobin Wang
Journal: Diabetes Care (2023)

To investigate the association of plasma insulin levels and their trajectories from birth to childhood with the timing of menarche.
Targeting PPAR-gamma counteracts tumour adaptation to immune-checkpoint blockade in hepatocellular carcinoma
Authors: Zhewen Xiong, Stephen Lam Chan, Jingying Zhou, Joaquim S.L. Vong, Tsz Tung Kwong, Xuezhen Zeng, Haoran Wu, Jianquan Cao, Yalin Tu, Yu Feng, Weiqin Yang, Patrick Pak-Chun Wong, Willis Wai-Yiu Si-Tou, Xiaoyu Liu, Jing Wang, Wenshu Tang, Zhixian Liang, Jiahuan Lu, Ka Man Li, Jie-Ting Low, Michael Wing-Yan Chan, Howard H.W. Leung, Anthony W.H. Chan, Ka-Fai To, Kevin Yuk-Lap Yip, Yuk Ming Dennis Lo, Joseph Jao-Yiu Sung, Alfred Sze-Lok Cheng
Journal: Gut (2023)

Objective Therapy-induced tumour microenvironment (TME) remodelling poses a major hurdle for cancer cure. As the majority of patients with hepatocellular carcinoma (HCC) exhibits primary or acquired resistance to antiprogrammed cell death (ligand)-1 (anti-PD-[L]1) therapies, we aimed to investigate the mechanisms underlying tumour adaptation to immune-checkpoint targeting. Design Two immunotherapy-resistant HCC models were generated by serial orthotopic implantation of HCC cells through anti-PD-L1-treated syngeneic, immunocompetent mice and interrogated by single-cell RNA sequencing (scRNA-seq), genomic and immune profiling. Key signalling pathway was investigated by lentiviral-mediated knockdown and pharmacological inhibition, and further verified by scRNA-seq analysis of HCC tumour biopsies from a phase II trial of pembrolizumab ( NCT03419481 ). Results Anti-PD-L1-resistant tumours grew &gt;10-fold larger than parental tumours in immunocompetent but not immunocompromised mice without overt genetic changes, which were accompanied by intratumoral accumulation of myeloid-derived suppressor cells (MDSC), cytotoxic to exhausted CD8 + T cell conversion and exclusion. Mechanistically, tumour cell-intrinsic upregulation of peroxisome proliferator-activated receptor-gamma (PPARγ) transcriptionally activated vascular endothelial growth factor-A (VEGF-A) production to drive MDSC expansion and CD8 + T cell dysfunction. A selective PPARγ antagonist triggered an immune suppressive-to-stimulatory TME conversion and resensitised tumours to anti-PD-L1 therapy in orthotopic and spontaneous HCC models. Importantly, 40% (6/15) of patients with HCC resistant to pembrolizumab exhibited tumorous PPARγ induction. Moreover, higher baseline PPARγ expression was associated with poorer survival of anti-PD-(L)1-treated patients in multiple cancer types. Conclusion We uncover an adaptive transcriptional programme by which tumour cells evade immune-checkpoint targeting via PPARγ/VEGF-A-mediated TME immunosuppression, thus providing a strategy for counteracting immunotherapeutic resistance in HCC.
Resolution of structural variation in diverse mouse genomes reveals chromatin remodeling due to transposable elements
Authors: Ardian Ferraj, Peter A. Audano, Parithi Balachandran, Anne Czechanski, Jacob I. Flores, Alexander A. Radecki, Varun Mosur, David S. Gordon, Isha A. Walawalkar, Evan E. Eichler, Laura G. Reinholdt, Christine R. Beck
Journal: Cell Genomics (2023)

Diverse inbred mouse strains are important biomedical research models, yet genome characterization of many strains is fundamentally lacking in comparison with humans. In particular, catalogs of structural variants (SVs) (variants ≥ 50 bp) are incomplete, limiting the discovery of causative alleles for phenotypic variation. Here, we resolve genome-wide SVs in 20 genetically distinct inbred mice with long-read sequencing. We report 413,758 site-specific SVs affecting 13% (356 Mbp) of the mouse reference assembly, including 510 previously unannotated coding variants. We substantially improve the
Internal Thoracic Vein Tumor Thrombus From Sternal Melanoma Metastasis on 18F-FDG PET/CT
Authors: Falko Ensle, Jan A. Schaab, Florentia Dimitriou, Martin W. Huellner, Alexander Maurer
Journal: Clinical Nuclear Medicine (2023)

We present 18 F-FDG PET/CT findings of an internal thoracic vein tumor thrombus from melanoma in a 76-year-old woman. Restaging 18 F-FDG PET/CT shows a progressive disease with an internal thoracic vein tumor thrombus from a sternal bone metastasis. Although cutaneous malignant melanoma may metastasize to any body part, a direct tumor invasion of veins and the formation of a tumor thrombus represent an extremely rare complication.
Machine learning predictions of MHC-II specificities reveal alternative binding mode of class II epitopes
Authors: Julien Racle, Philippe Guillaume, Julien Schmidt, Justine Michaux, Amédé Larabi, Kelvin Lau, Marta A.S. Perez, Giancarlo Croce, Raphaël Genolet, George Coukos, Vincent Zoete, Florence Pojer, Michal Bassani-Sternberg, Alexandre Harari, David Gfeller
Journal: Immunity (2023)

CD4+ T cells orchestrate the adaptive immune response against pathogens and cancer by recognizing epitopes presented on class II major histocompatibility complex (MHC-II) molecules. The high polymorphism of MHC-II genes represents an important hurdle toward accurate prediction and identification of CD4+ T cell epitopes. Here we collected and curated a dataset of 627,013 unique MHC-II ligands identified by mass spectrometry. This enabled us to precisely determine the binding motifs of 88 MHC-II alleles across humans, mice, cattle, and chickens. Analysis of these binding specificities combined with X-ray crystallography refined our understanding of the molecular determinants of MHC-II motifs and revealed a widespread reverse-binding mode in HLA-DP ligands. We then developed a machine-learning framework to accurately predict binding specificities and ligands of any MHC-II allele. This tool improves and expands predictions of CD4+ T cell epitopes and enables us to discover viral and bacterial epitopes following the aforementioned reverse-binding mode.
Characterization of Bone Marrow Niche in Chronic Myeloid Leukemia Patients Identifies CXCL14 as a New Therapeutic Option
Authors: Monika Dolinska, Huan Cai, Alma Mansson, Jingyi Shen, Pingnan Xiao, Thibault Bouderlique, Xidan Li, Elory Leonard, Marcus Chang, Yuchen Gao, Juan Pablo Medina Giménez, Makoto Kondo, Lakshmi Sandhow, Anne-Sofie Johansson, Stefan Deneberg, Stina Söderlund, Martin Jädersten, Johanna S Ungerstedt, Magnus Tobiasson, Arne Östman, Satu Mustjoki, Leif Stenke, Katarina Le Blanc, Eva S Hellstrom-Lindberg, Sören Lehmann, Marja Ekblom, Ulla Olsson-Strömberg, Mikael Sigvardsson, Hong Qian
Journal: Blood (2023)

Although tyrosine kinase inhibitors are effective for treating chronic myeloid leukemia (CML), they often fail to eradicate the leukemia-initiating stem cells (LSCs), causing disease persistence and relapse. Evidence indicates that LSC persistence may be due to bone marrow (BM) niche protection. However, little is known about the underlying mechanisms. We here molecularly and functionally characterized BM niches in CML patients at diagnosis and revealed the altered niche composition and function in the CML patients. Long-term culture initiating cell (LTC-IC) assay showed that the mesenchymal stem cells from CML patients displayed an enhanced supporting capacity for normal and CML BM CD34+CD38- cells. Molecularly, RNA sequencing detected dysregulated cytokine and growth factor expression in CML patient BM cellular niches. Among them, CXCL14 was lost in the BM cellular niches in contrast to its expression in healthy BM. Restoring CXCL14 significantly inhibited CML LSC maintenance and enhanced their response to imatinib in vitro, and CML engraftment in vivo in NSG-SGM3 mice. Importantly, CXCL14 treatment dramatically inhibited CML engraftment in xenografted NSG-SGM3 mice, even to a greater degree than imatinib, and this inhibition persisted in patients with suboptimal TKI response. Mechanistically, CXCL14 upregulated inflammatory cytokine signaling but downregulated mTOR signaling and oxidative phosphorylation in CML LSCs. Together, we have discovered a suppressive role of CXCL14 in CML LSC growth. CXCL14 might offer a treatment option targeting CML LSCs.
Consensus Molecular Subtypes as Biomarkers of Fluorouracil and Folinic Acid Maintenance Therapy With or Without Panitumumab in <i>RAS</i> Wild-Type Metastatic Colorectal Cancer (PanaMa, AIO KRK 0212)
Authors: Arndt Stahler, Beeke Hoppe, Il-Kang Na, Luisa Keilholz, Lothar Müller, Meinolf Karthaus, Stefan Fruehauf, Ullrich Graeven, Ludwig Fischer von Weikersthal, Eray Goekkurt, Stefan Kasper, Andreas Jay Kind, Annika Kurreck, Annabel Helga Sophie Alig, Swantje Held, Anke Reinacher-Schick, Volker Heinemann, David Horst, Armin Jarosch, Sebastian Stintzing, Tanja Trarbach, Dominik Paul Modest
Journal: Journal of Clinical Oncology (2023)

Consensus molecular subtypes (CMSs) were evaluated as prognostic and predictive biomarkers of patients with RAS wild-type metastatic colorectal cancer (mCRC) receiving fluorouracil and folinic acid (FU/FA) with or without panitumumab (Pmab) after Pmab + mFOLFOX6 induction within the randomized phase II PanaMa trial.CMSs were determined in the safety set (ie, patients that received induction) and full analysis set (FAS; ie, randomly assigned patients who received maintenance) and correlated with median progression-free survival (PFS) and overall survival (OS) since the start of induction or maintenance treatment and objective response rates (ORRs). Hazard ratios (HRs) and 95% CI were calculated by univariate/multivariate Cox regression analyses.Of 377 patients of the safety set, 296 (78.5%) had available CMS data: CMS1/2/3/4: 29 (9.8%)/122 (41.2%)/33 (11.2%)/112 (37.8%) and unclassifiable: 17 (5.7%). The CMSs were prognostic biomarkers in terms of PFS (P < .0001), OS (P < .0001), and ORR (P = .02) since the start of induction treatment. In FAS patients (n = 196), with CMS2/4 tumors, the addition of Pmab to FU/FA maintenance therapy was associated with longer PFS (CMS2: HR, 0.58 [95% CI, 0.36 to 0.95], P = .03; CMS4: HR, 0.63 [95% CI, 0.38 to 1.03], P = .07) and OS (CMS2: HR, 0.88 [95% CI, 0.52 to 1.52], P = .66; CMS4: HR, 0.54 [95% CI, 0.30 to 0.96], P = .04). The CMS interacted significantly with treatment in terms of PFS (CMS2 v CMS1/3: P = .02; CMS4 v CMS1/3: P = .03) and OS (CMS2 v CMS1/3: P = .03; CMS4 v CMS1/3: P < .001).The CMS had a prognostic impact on PFS, OS, and ORR in RAS wild-type mCRC. In PanaMa, Pmab + FU/FA maintenance was associated with beneficial outcomes in CMS2/4, whereas no benefit was observed in CMS1/3 tumors.
Radiosensitisation by olaparib through focused ultrasound delivery in a diffuse midline glioma model
Authors: E. ’t Hart, J. Bianco, M.A.C. Bruin, M. Derieppe, H.C. Besse, K. Berkhout, L.A. Chin Joe Kie, Y. Su, E.W. Hoving, A.D.R. Huitema, M.G. Ries, D.G. van Vuurden
Journal: Journal of Controlled Release (2023)

Diffuse midline glioma H3K27-altered (DMG) is an aggressive, inoperable, predominantly paediatric brain tumour. Treatment strategies are limited, resulting in a median survival of only 11 months. Currently, radiotherapy (RT), often combined with temozolomide, is considered the standard of care but remains palliative, highlighting the urgency for new therapies. Radiosensitisation by olaparib, an inhibitor of PARP1 and subsequently PAR-synthesis, is a promising treatment option. We assessed whether PARP1 inhibition enhances radiosensitivity in vitro and in vivo following focused ultrasound mediated blood-brain barrier opening (FUS-BBBO).Effects of PARP1 inhibition were evaluated in vitro using viability, clonogenic, and neurosphere assays. In vivo olaparib extravasation and pharmacokinetic profiling following FUS-BBBO was measured by LC-MS/MS. Survival benefit of FUS-BBBO combined with olaparib and RT was assessed using a patient-derived xenograft (PDX) DMG mouse model.Treatment with olaparib in combination with radiation delayed tumour cell proliferation in vitro through the reduction of PAR. Prolonged exposure of low olaparib concentration was more efficient in delaying cell growth than short exposure of high concentration. FUS-BBBO increased olaparib bioavailability in the pons by 5.36-fold without observable adverse effects. A Cmax of 54.09 μM in blood and 1.39 μM in the pontine region was achieved following administration of 100 mg/kg olaparib. Although RT combined with FUS-BBBO mediated olaparib extravasation delayed local tumour growth, survival benefits were not observed in an in vivo DMG PDX model.Olaparib effectively radiosensitises DMG cells in vitro and reduces primary tumour growth in vivo when combined with RT. Further studies are needed to investigate the therapeutic benefit of olaparib in suitable preclinical PDX models.
Incidental Meningioma With Altered PSMA Expression After Systemic Hormone Therapy and Local Radiotherapy Detected by 68Ga-PSMA PET/CT
Authors: Fatih Tamer, Ozgur Omur
Journal: Clinical Nuclear Medicine (2023)

Abstract A 59-year-old man underwent radical prostatectomy for adenocarcinoma in 2009. Because of the progression of PSA levels, a 68 Ga-PSMA PET/CT scan was performed in January 2020. A suspicious uptake was detected in the left cerebellar hemisphere, and there was no evidence of distant metastatic disease other than recurrent malignancy in the prostatectomy bed. MRI revealed a meningioma located in the left cerebellopontine angle. Although PSMA uptake of the lesion increased in the first imaging after hormone therapy, partial regression was noted after radiotherapy applied to this region.
Pazopanib in Locally Advanced or Metastatic Renal Cell Carcinoma: Results of a Randomized Phase III Trial
Authors: Cora N. Sternberg, Ian D. Davis, Jozef Mardiak, Cezary Szczylik, Eunsik Lee, John Wagstaff, Carlos H. Barrios, Pamela Salman, Oleg A. Gladkov, Alexander Kavina, Juan J. Zarbá, Mei Chen, Lauren McCann, Lini Pandite, Debasish F. Roychowdhury, Robert E. Hawkins
Journal: Journal of Clinical Oncology (2023)

Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit. This randomized, double-blind, placebo-controlled phase III study evaluated efficacy and safety of pazopanib monotherapy in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma (RCC).
Role of 68Ga-FAPI PET/CT in Assessing Hepatobiliary Malignancies
Authors: Vishnukumar Rajaraman, Lakshman Aridhasan Meenakshi, Ashwin Jeba Selvaraj, Biju Pottakkat, Dhanapathi Halanaik
Journal: Clinical Nuclear Medicine (2023)

Introduction and Aim Preliminary studies showed good expression of fibroblast activating protein inhibitor (FAPI) in hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). Our aims were to study the diagnostic performance of 68 Ga-FAPI PET/CT in diagnosing the primary hepatobiliary malignancies and to compare its performance with 18 F-FDG PET/CT. Patients and Methods Patients suspected to have HCC and CC were recruited prospectively. FDG and FAPI PET/CT studies were completed within 1 week. Final diagnosis of malignancy was achieved by tissue diagnosis (either histopathological examination or fine-needle aspiration cytology) and radiological correlation from conventional modalities. Results were compared with final diagnosis and expressed as sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy. Results Forty-one patients were included. Thirty-one were positive for malignancy and 10 were negative. Fifteen were metastatic. Of 31, 18 were CC and 6 were HCC. For overall diagnosis of the primary disease, FAPI PET/CT performed exceptionally compared with FDG PET/CT with sensitivity, specificity, and accuracy of 96.77%, 90%, and 95.12%, respectively, versus 51.61%, 100%, and 63.41% for FDG PET/CT. FAPI PET/CT clearly outperformed FDG PET/CT for the evaluation of CC with sensitivity, specificity, and accuracy of 94.4%, 100%, and 95.24%, respectively, whereas for FDG PET/CT sensitivity, specificity, and accuracy were 50%, 100%, and 57.14%, respectively. Diagnostic accuracy of FAPI PET/CT was 61.54% for metastatic HCC compared with 84.62% for FDG PET/CT. Conclusions Our study highlights the potential role of FAPI-PET/CT in evaluating CC. It also ascertains its usefulness in the cases of mucinous adenocarcinoma. Although it showed a higher lesion detection rate than FDG in primary HCC, its diagnostic performance in the metastatic setting is questionable.
Outcomes of Patients With Classic Hodgkin Lymphoma Who Relapsed After Autologous Stem Cell Transplant
Authors: Aung M. Tun, Yucai Wang, Aasiya Matin, David J. Inwards, Thomas M. Habermann, Ivana Micallef, Patrick B. Johnston, Luis Porrata, Jonas Paludo, Jose Villasboas Bisneto, Allison Rosenthal, Han W. Tun, James R. Cerhan, Thomas E. Witzig, Grzegorz S. Nowakowski, Stephen M. Ansell
Journal: HemaSphere (2023)

Immune checkpoint inhibitors (ICIs) and brentuximab vedotin (BV) are novel agents for classic Hodgkin lymphoma, including relapse after autologous stem cell transplant (ASCT). However, their impact on survival post-ASCT relapse, in comparison with conventional therapy, is less known due to the lack of randomized controlled trials. Clinical characteristics and outcomes of 115 patients with relapse (or progression) after ASCT are studied. After a median follow-up of 8.59 years from post-ASCT relapse, the median progression-free survival (PFS) and overall survival (OS) were 0.91 and 5.07 years, respectively. Median lines of therapy after post-ASCT relapse was 2 (range, 1-12). The median PFS was not reached (NR) versus 1.11 versus 0.50 versus 0.85 versus 0.78 years (